Although beta-receptor antagonists have been proven effective in preventing sudden death and suppressing ventricular arrhythmias, both actions of these drugs are poorly understood. The possible contribution of non-beta-receptor-mediated electrophysiologic changes demonstrable in vitro is controversial. Our initial observation that a subset of patients required plasma propranolol concentrations for suppression of ventricular arrhythmias well in excess of those producing substantial beta-blockade led us to hypothesize that propranolol produced electrophysiologic effects in vivo independant of beta-blockade. Subsequent animal work provided support for this hypothesis since isoproterenol did not reverse all of propranolol's electrophysiologic effects. Comparison of the electrophysiologic effects of low and high plasma propranolol concentrations in patients indicated the presence of such a non-beta-receptor-mediated effect in man. In animal models and in human volunteers these electrophysiologic changes were produced by the d-isomer of propranolol and proven to be unrelated to its weak beta-blocking action. To further evaluate the possible role of non-beta-mediated actions of other beta-blockers, we assessed the dose-antiarrhythmic relationships of timolol and sotalol in patients with ventricular arrhythmias. Timolol, an agent whose effects are thought to be mediated exclusively by beta-blockade, was effective in only a minority of patients and incremental efficacy beyond that produced by beta-blockade was not demonstrable. On the other hand, a subset of patients with beta-blocker-resistant arrhythmias was found to respond to sotalol, a beta-blocker with the additional property of refractory period prolongation similar to the highly effective and frequently toxic agent, amiodarone. We will now extend our electrophysiologic observations to evaluate the antiarrhythmic efficacy of the d-isomers of propranolol and sotalol. Preliminary data indicate that d-propranolol can effectively suppress ventricular arrhythmias in man without producing clinically significant beta-blockade. Both d-propranolol and d-sotalol will be evaluated in this patient population as well as in patients with sustained ventricular tachycardia inducible by programmed stimulation. Racemic and d-sotalol (at concentrations producing equal suppression of isoproterenol-induced tachycardia) will be compared in a canine model of inducible sustained ventricular tachycardia. To assess the clinical significance of sotalol's non-beta-mediated refractory period prolongation, sotalol will be substituted for amiodarone in patients with life-threatening arrhythmias. The proposed studies will evaluate the importance of the non-beta-mediated effects of this class of drugs and so allow design of safer and better tolerated therapies for ventricular arrhythmias and sudden cardiac death.